The heart is one of the least regenerative organs in mammals, but this actually isn’t the case in every circumstance; some types of injury and stimulus do produce a greater regenerative response, even if nowhere near as large as desired. The suspicion is that the capacity for greater regenerative exists, but is muted in some way, perhaps by cancer suppression mechanisms such as the ARF gene. Thus researchers are hunting for clues in the biochemistry of more regenerative species, such as zebrafish and salamanders, in order to discover whether or not mammalian heart cells can be adjusted to heal injuries more readily. Another place to look, as illustrated here, is in the biochemistry of the few circumstances in which mammalian hearts are known to regenerate more readily.
In adult mammal hearts, cardiomyoctyes do not proliferate following damage, like that caused by myocardial infarction. However, the inability to proliferate is not true for all animals, and even in mammals, cardiomyocyte proliferation is known. Neonatal cardiomyocytes proliferate, and the cardiomyocytes of zebrafish proliferate through adulthood, for example. However, hearts recover well from myocarditis, suggesting adult cardiomyocytes can proliferate in certain conditions. Myocarditis describes inflammation of the heart, usually in response to a viral infection. Many patients will suffer from cardiac dysfunction but recover naturally, largely because of factors activated by the immune response.
Researchers prepared mice with myocarditis to investigate this recovery under the assumption that proliferation was not the cause. “We hypothesized that immune factors are responsible. STAT3 is a transcription factor with cardioprotective effects. But in our study, we found it also has cardioproliferative effects. In myocarditis, we found that STAT3 was activated and that cardiomyocytes could proliferate. But when we knocked-out STAT3, the proliferation was lost.” For cells to proliferate, they must enter the cell cycle. Following birth, mammalian cardiomyoctyes exit the cell cycle. The researchers found that in myocarditis, cardiomyoctyes could reenter the cycle to proliferate and recover heart function.
In myocarditis about 1% of cardiomyocytes express Aurora B, an indicator of cells entering the cell cycle, but in myocardial infarction (heart attacks) only 0.01% of cardiomyocytes expressed Aurora B. The team also found that the activation of STAT3 and expression of cell cycle markers could be stimulated by the immune protein interleukin 11, suggesting a possible cytokine means to initiate the proliferation. “These were very surprising findings. We still have much to learn about how the inflammatory signaling can promote heart regeneration. Medicines that activates these pathways could lead to new cardiac drugs.”